Our goal in this continuing Program Project is still to facilitate the transfer of basic science information from the laboratory to help deal with clinical problems in breast cancer, but our focus broadens from primarily prognostic and mechanistic considerations in two directions. First, we will study the molecular correlates of the developmental stages in early breast cancer, to provide not only greater understanding of how the full malignant phenotype is acquired, but also greater clinical ability to distinguish and thus to treat those benign or early malignant lesions destined to cause serious trouble. Second, at the other end of the clinical course, we will be dissecting the components of growth factor pathways as potential targets of new treatment strategies and testing such strategies directly in preclinical model systems. The projects will study: 1) the problem of how best to integrate both new and existing prognostic factors into a coherent assessment of risk for individual patients, comparing expanded forms of the traditional Cox multivariate analysis with newer recursive partitioning and artificial intelligence (neural network) approaches; 2) the occurrence of mutations and variants in the functional domains of the steroid receptor genes, which could result in failures to respond to hormone manipulation even though receptor is present, or in failure to detect receptor, or even in an oncogene-like receptor variant which would stimulate the tumor cell even in the absence of hormone; 3) potential molecular markers -- activated oncogenes, proliferation markers, antigens associated with metastatic behavior, etc.--in well defined early and later lesions at several stages, in order to see which markers might identify high risk lesions and to learn more about the evolutionary pathway (or pathways) by which breast cancer progresses; 4) antigens associated with proliferation as new prognostic as new prognostic markers; 5) TGFalpha as an autocrine mediator of estrogen action, as a factor in the development of hyperplastic lesions in transgenic mice expressing a TGFalpha gene (and/or an EGF-R gene) in the mammary glands, and as a target for inhibiting malignant progression; 6) the insulin-like growth factor (IGF) system, especially the receptors, IGFRI and IGFRII and the IGF binding proteins, as targets for blocking breast cancer growth and tumorigenesis. These projects will all be supported by a tumor/data network core function, flow cytometry, factor assay, and tissue culture core laboratories, and an administrative core. Many of the factors and markers studied in these interactive projects will have important clinical significance. Indeed, our major effort will be to help oncologists integrate and appropriately utilize basic science information in the 1990's in diagnostic and treatment strategies for the breast cancer patient.